Neuropathic pain can be classified as peripheral and central neuropathic pain. Peripheral neuropathic pain is caused by injury or infection of peripheral sensory nerves, whereas central neuropathic pain is caused by damage to the CNS and/or the spinal cord. Both peripheral and central neuropathic pain can occur without obvious initial nerve damage.
A similar definition is given by the International Association for the Study of Pain (IASP, Seattle, Wash., USA): peripheral neuropathic pain is pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system. Central neuropathic pain is pain initiated or caused by a primary lesion or dysfunction in the central nervous system.
Peripheral lesions may be lesions of perpherial nerves, e.g. diabetic neuropathy, drug-inducted neuropathy, e.g. upon chemotherapy, lesions of nerve roots and posterior ganglia, e.g. post-herpetic neuralgia or nerve root avulsions, neuropathic cancer pain due to compression of peripheral nerves, nerve plexuses and nerve roots, etc. Central lesions may be lesions due to infarction, compressive tumors or abscesses, e.g. in the brainstem, or may be spinal cord lesions due to injury or operations (Jain K K, Emerging Drugs, 2000, 5:241-257; McQuay, 2002, European Journal of Pain 6 (Suppl. A): 11-18).
The above examples of peripheral and central neuropathic pain demonstrate that peripheral and central neuropathic pain are distinguished not only by the anatomical location of the lesion or dysfunction, but they also demonstrate that peripheral and central neuropathic pain can be distinguished by its mechanisms (McQuay, supra). Consequently, there is no clear relation between drug action mechanism and the effect in distinct pain conditions or for single drug classes and different pain conditions (Sindrup S H, Jensen T S, Pain 1999, 83:389-400).
Common analgesics like opioids and non-steroidal anti-inflammatory drugs (NSAIDs) improve only insufficiently chronic abnormal pain syndromes as peripheral and central neuropathic pain due to insufficient efficacy and/or dose-limiting side effects. In the search for alternative treatment regimes to produce satisfactory and sustained pain relief, corticosteroids, conduction blockade, glycerol, anti-convulsants, anti-arrhythmics, antidepressants, local anesthetics, topical agents such as capsaicin, gangliosides and electrostimulation have been tried, but only a subset of patients with neuropathic pain respond to such treatments and typically, significant pain remains even in these responders. The critical issue with current therapies is the therapeutic window; a particular treatment might have potential for efficacy but the patients are not ‘treated to effect’ because of limiting side effects upon dose escalation.
Central neuropathic pain is a form of neuropathic pain which is a particularly difficult form to be treated (Yezierski and Burchiel, 2002). Due to lesions in the spinothalamocortical pathways, ectopic neuronal discharges can occur in different neurons of the spinal cord and brain. Hyperexcitability in damaged areas of the central nervous system plays a major role in the development of central neuropathic pain. Patients with central neuropathic pain almost always have stimulus-independent pain. In addition, in the case of spinal cord injury, for example, stimulus-dependent pain may be present, usually because skin areas or viscera below the lesions are allodynic. Thus, partial spinal lesions may tend to produce pain to a greater extent than do complete lesions.
Other accepted forms of central neuropathic pain or diseases associated with central neuropathic pain exist. Examples include inflammatory CNS diseases such as multiple sclerosis, myelitis or syphilis, ischemia, hemorrhages or asteriovenous malformations (e.g. post-stroke neuropathic pain) located in the thalamus, spinothalamic pathway or thalamocortical projections, and syrnigomyelia (Koltzenburg, Pain 2002—An Updated Review: Refresher Course Syllabus; IASP Press, Seattle, 2002).
Na+-channels are central to the generation of action potentials in all excitable cells such as neurons and myocytes. As such they play key roles in a variety of disease states such as pain (See, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels and pain” Proc Natl Acad Sci USA 96(14): 7635-9 and Waxman, S. G., T. R. Cummins, et al. (2000) “Voltage-gated sodium channels and the molecular pathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28). Three members of the gene family (NaV1.8, 1.9, 1.5) are resistant to block by the well-known Na channel blocker TTX, demonstrating subtype specificity within this gene family. Mutational analysis has identified glutamate 387 as a critical residue for TTX binding (See, Noda, M., H. Suzuki, et al. (1989) “A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II” FEBS Lett 259(1): 213-6).
In general, voltage-gated sodium channels (NaVs) are responsible for initiating the rapid upstroke of action potentials in excitable tissue in nervous system, which transmit the electrical signals that compose and encode normal and aberrant pain sensations. Antagonists of NaV channels can attenuate these pain signals and are useful for treating a variety of pain conditions, including but not limited to acute, chronic, inflammatory, and neuropathic pain. Known NaV antagonists include TTX, lidocaine (See Mao, J. and L. L. Chen (2000) “Systemic lidocaine for neuropathic pain relief” Pain 87(1): 7-17.) bupivacaine, carbamazepine, mexilitene, phenytoin (See Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8), and lamotrigine (See Rozen, T. D. (2001) “Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia” Headache 41 Suppl 1:S25-32 and Jensen, T. S. (2002). However, side effects include dizziness, somnolence, nausea and vomiting (See Tremont-Lukats, I. W., C. Megeff, and M. M. Backonja (2000) “Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy” Drugs 60:1029-1052) that limit the utility of these known NaV antagonists for the treatment of pain. These side effects are thought to result at least in part from the block of multiple NaV subtypes. An agent that inhibits the NaV1.8 channel selectively would provide a much great therapeutic window than these non-selective, known NaV antagonists.
The detection and transmission of nociceptive stimuli is mediated by small sensory neurons. Immunohistochemical, in-situ hybridization and electrophysiology experiments have all shown that the sodium channel NaV1.8 is selectively localized to the small sensory neurons of the dorsal root ganglion and trigeminal ganglion (see Akopian, A. N., L. Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons” Nature 379(6562): 257-62.). After experimental nerve injury, immunohistochemical data demonstrated an accumulation of Nav1.8 at the site of nerve injury, concomitant with an upregulation in TTX-resistant sodium current, consistent with NaV1.8 as a mechanism underlying hyperalgesia (see Gold, M. S., D. Weinreich, et al. (2003) “Redistribution of Nav1.8 in uninjured axons enables neuropathic pain” J. Neurosci. 23:158-166). Attenuation of NaV1.8 expression with antisense oligodeoxynucleotides administered by intrathecal injection prevented experimental nerve-injury induced redistribution of Nav1.8 in the sciatic nerve and reversed neuropathic pain (tactile and thermal hyperalgesia), demonstrating a causal role of Nav1.8 in nerve-injury induced pain (see also Lai, J., M. S. Gold, et al. (2002) “Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain 95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade of neuropathic pain by antisense targeting of tetrodotoxin-resistant sodium channels in sensory neurons” Methods Enzymol 314: 201-13.). In inflammatory pain models, intrathecal administration of antisense oligodeoxynucleotides against NaV1.8 resulted in a significant reduction in PGE2-induced hyperalgesia (see Khasar, S. G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20) and in CFA (complete Freund's adjuvant)—induced hyperalgesia (Porreca, F., J. Lai, et al. (1999) “A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain” Proc. Nat'l. Acad. Sci. 96: 7640-7644). In addition, in a rat model of visceral pain, induced by intravesical infusion of acetic acid, bladder hyperactivity was reduced by intrathecal injection of antisense oligodeoxynucleotides against NaV1.8, showing that Nav1.8 contributes to the activation of sensory nerves in visceral pain (Yoshimura, N., S. Seki, et al. (2001) “The involvement of the tetrodotoxin-resistant sodium channel Nav1.8 (PN3/SNS) in a rat model of visceral pain” J. Neurosci. 21: 8690-8696).
Taken together, these data support a role for NaV1.8 in the detection and transmission of inflammatory and neuropathic pain.
Recently, double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). WO 99/32619 (Fire et al.) discloses the use of a dsRNA of at least 25 nucleotides in length to inhibit the expression of the Nav1.8 gene in C. elegans. dsRNA has also been shown to degrade target RNA in other organisms, including plants (see, e.g., WO 99/53050, Waterhouse et al.; and WO 99/61631, Heifetz et al0.), Drosophila (see, e.g., Yang, D., et al., Curr. Biol. (2000) 10:1191-1200), and mammals (see WO 00/44895, Limmer; and DE 101 00 586.5, Kreutzer et al.). This natural mechanism has now become the focus for the development of a new class of pharmaceutical agents for treating disorders that are caused by the aberrant or unwanted regulation of a gene.
Despite significant advances in the field of RNAi and advances in the treatment of pain, there remains a need for an agent that can selectively and efficiently silence the Nav1.8 gene using the cell's own RNAi machinery that has both high biological activity and in vivo stability, and that can effectively inhibit expression of a target Nav1.8 gene for use in treating pain.